Method for the synthesis of unsymmetrical tertiary amines

ABSTRACT

Disclosed is a new method for the synthesis of unsymmetrical tertiary amines using alcohol and an imine, and to new tertiary amines.

The present invention relates to a new method for the synthesis ofunsymmetrical tertiary amines using an alcohol and an imine, as well asnovel tertiary amines.

The development of simple reactions for C—N bond formation is animportant challenge to chemists. Substituted amines have widespreadapplications in the synthesis of drugs, dyes, detergents, perfumes,pharmaceuticals, emulsifiers, crop protection agents, etc.

Among the various strategies for the synthesis of amines, thedevelopment of direct amination reactions of alcohols for the rapidgeneration of secondary or tertiary amines, from simple and readilyavailable starting materials, is at the forefront of fine chemicalsynthesis and involves a high potential for industrial development.

Among these methods, the direct amination of alcohols by borrowing ofhydrogen (or hydrogen transfer) has been recognized as one of the mostpractical for the industrial production of trisubstituted alkylamines.This atom efficient reaction and the wide availability of the alcohols,combined with the fact that water is the only byproduct of thesereactions, responding to general principles of green chemistry, are thereasons for its widespread use.

This amination has been performed for the first time with latetransition metals of the second and third periods, which were rapidlyfollowed by much more elaborate complexes (Ru, Rh, Ir, Os). The currenttrend is to replace these noble elements with less expensive and moreabundant transition metals of the first period. In this respect,significant improvements have recently been made using manganese, ironor cobalt catalysts. However, there is still a significant need for moreactive catalysts working in milder conditions, which allow greaterfunctional tolerance of the substrate and improve the selectivity andTON (Turn-Over Number).

If we wish to access the synthesis of tertiary amines by this strategy,we can only have access to trisubstituted amines with 1 or 2 differentgroups. However, there are no direct amination methods to accesstertiary amines having 3 different substituents. The direct conversionof primary amines, via the synthesis of imines, to tertiary aminesbearing three different substituents is thus unknown to date.

One of the aims of the invention is the provision of a new method forthe synthesis of tertiary trisubstituted asymmetric amines, simple toimplement, fast and applicable to a wide variety of substrates.

One of the other aims of the invention is the possibility of using acatalyst derived from an abundant and inexpensive metal allowing to workunder mild conditions.

One of the other aims of the invention is the ability to access thesynthesis of a wide variety of tertiary amines, in a simple manner.

This new method has the advantages of being simple to implement, fast,applicable to a wide variety of substrates, using a catalyst derivedfrom an abundant and inexpensive metal and allowing to work under mildconditions.

The present invention relates to the use of an alcohol, in particularprimary or secondary, with the exception of methanol, and of an imine inthe implementation of a method of preparation of tertiary amines.

Within the meaning of the invention, the expression “primary alcohol”refers to a compound of formula R—O—H wherein the carbon atom carryingthe hydroxyl group also carries two hydrogen atoms.

Within the meaning of the invention, the expression “secondary alcohol”refers to a compound of formula R—O—H wherein the carbon atom carryingthe hydroxyl group carries a single hydrogen atom.

Within the meaning of the invention, the expression “tertiary amine”refers to a compound of formula N—R₃ in which R is not a hydrogen atom.

The present invention also relates to the use of an alcohol, inparticular primary or secondary, with the exception of methanol, and ofan imine in the implementation of a method of preparation of tertiaryamines, in particular carrying three different substituents.

According to another embodiment, the invention relates to the use of analcohol, in particular primary or secondary, with the exception ofmethanol, and of an imine in the implementation of a method ofpreparation of tertiary amines, wherein the prepared tertiary aminecarries three all different substituents with respect to each other anddifferent from a hydrogen atom.

According to another embodiment, the invention relates to the use of analcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl andof an imine of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,in the implementation of a method of preparation of tertiary amines offormula (E)

wherein R₁, R₂, R₃, R₄ are as defined above.

Within the meaning of the invention, the expression “C₁ to C₁₀” refersto an acyclic saturated carbon chain, linear or branched, comprising 1to 10 carbon atoms. Examples of C₁ to C₁₀ alkyls include methyl, ethyl,propyl, butyl, pentyl, hexyl or heptyl.

Within the meaning of the invention, the expression “C₂ to C₁₀” refersto an acyclic saturated carbon chain, linear or branched, comprising 2to 10 carbon atoms. Examples of C₂ to C₁₀ alkyls include ethyl, propyl,butyl, pentyl, hexyl or heptyl. The definition of propyl, butyl, pentyl,hexyl or heptyl includes all possible isomers. For example, the termbutyl comprises n-butyl, iso-butyl, sec-butyl and tert-butyl. The alkylmay be substituted at different positions with one or more functionalgroups such as halogen, alkoxyl, amino, nitro, cyano, trifluoromethyl orcarboxylic ester.

Within the meaning of the present invention, the expression “C₃ to C₁₀cycloalkyl” denotes a mono-, bi- or tri-cycle, saturated or partiallysaturated, comprising from 3 to 10 carbon atoms.

Within the meaning of the invention, the expression “C₁ to C₁₀ carbonylderivative” denotes a compound comprising 1 to 10 carbon atoms andhaving a double bond between a carbon atom and an oxygen atom.

Within the meaning of the invention, the expression “C₃ to C₁₀ formate”means a compound of formula HCOOR comprising 3 to 10 carbon atoms.

According to the above embodiment, the invention relates to the use ofan alcohol of formula (C), that can be a primary or secondary alcohol,and of an imine of formula (D), that can be an aldimine or a ketimine.

Within the meaning of the invention, the expression “aldimine” denotesan imine of formula (D)

wherein R₂ represents a hydrogen.

Within the meaning of the invention, the expression “ketimine” denotesan imine of formula (D)

wherein R₂ is not a hydrogen atom.

According to a particular embodiment, the invention relates to the useof a primary alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyland of an imine of formula (D)

wherein R₁ represents an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ to C₁₀cycloalkyl,R₂ represents a hydrogen,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,in the implementation of a method of preparation of tertiary amines offormula (E)

wherein R₁, R₂, R₃, R₄ are as defined above.

According to another particular embodiment, the invention relates to theuse of a primary alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl,and of an imine of formula (D)

wherein R₁ and R₂ represent an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ toC₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,in the implementation of a method of preparation of tertiary amines offormula (E)

wherein R₁, R₂, R₃, R₄ are as defined above.

According to another particular embodiment, the invention relates to theuse of a secondary alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl, andof an imine of formula (D)

wherein R₁ represents an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ to C₁₀cycloalkyl,R₂ represents a hydrogen,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative of, or a C₃ to C₁₀ formate,in the implementation of a method of preparation of tertiary amines offormula (E)

wherein R₁, R₂, R₃, R₄ are as defined above.

According to another particular embodiment, the invention relates to theuse of a secondary alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl,and of an imine of formula (D)

wherein R₁ and R₂ represent an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ toC₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,in the implementation of a method of preparation of tertiary amines offormula (E)

wherein R₁, R₂, R₃, R₄ are as defined above.

According to another embodiment, the invention relates to the use of analcohol, in particular primary or secondary, and of an imine in theimplementation of a method of preparation of tertiary amines wherein thepreparation of tertiary amines is performed in the presence of acatalyst comprising an iron(0) complex.

Within the meaning of the invention, the expression “catalyst” refers toa compound that allows, increases the speed of a chemical reaction.

Within the meaning of the invention, the expression “iron(0) complex”denotes a chemical structure in which an iron atom in the oxidationstate 0 is linked to multiple ligands.

Indeed, the inventors were able to go beyond the conventional reactivityof alcohols using iron(0) catalysts which are able to catalyze theaddition of primary alcohols and secondary on imines by N-alkylation.This method has no literature precedent and allows for the synthesis ofamines trisubstituted with three different groups, that are inaccessibleby conventional methods.

According to another embodiment, the invention relates to the use of analcohol, in particular primary or secondary, and of an imine in theimplementation of a method of preparation of tertiary amines, whereinthe preparation of tertiary amines is performed in the presence of acatalyst comprising an iron(0) complex chosen from the followingformulas:

in whichTs=tosyl

TMS=trimethylsilyl

TBDMS=tert-butyldimethylsilyl

TIPS=triisopropylsilyl

and preferably being of the following formula (B):

in whichTBDMS=tert-butyldimethylsilyl

Ts=tosyl

The catalyst used is either the catalyst of formula (B) prepared priorto the preparation of the tertiary amines, or the catalyst formed insitu during this preparation via the addition of trimethylamine oxide tothe complex of formula (A):

This cyclopentadienone tricarbonyl-type catalyst of formula (A) mustfirst be activated by the addition of an additive, trimethylamine oxide,to remove a CO type ligand, which makes it active but this step requiresthe use of a glove box. The inventors have demonstrated that thepreformed catalyst of formula (B), through stabilization of anacetonitrile ligand, could be manipulated in ambient air, and wasequally active in catalysis.

According to another embodiment, the invention relates to the use of analcohol, in particular primary or secondary, and of an imine, in theimplementation of a method of preparation of tertiary amines wherein thepreparation of tertiary amines is performed in the presence of acatalyst comprising an iron(0) complex chosen from the followingformulas:

in whichTs=tosyl

TMS=trimethylsilyl

TBDMS=tert-butyldimethylsilyl

TIPS=triisopropylsilyl

and preferably being of the following formula (B):

in whichTBDMS=tert-butyldimethylsilyl

Ts=tosyl

Other examples of catalysts that can be used are the following:

According to another embodiment, the invention relates to the use of analcohol, in particular primary or secondary, and of an imine in theimplementation of a method of preparation of tertiary amines wherein thepreparation of amino tertiary is performed in the presence of a catalystcomprising an iron(0) complex, wherein the catalyst used is either thecomplex of formula (B) formed prior to the preparation of tertiaryamines, or the catalyst formed in situ during said preparation oftertiary amines by adding trimethylamine oxide to the complex of formula(A):

According to a particular embodiment, the invention relates to the useof an alcohol, in particular primary or secondary, and of an imine inthe implementation of a tertiary amine preparation method, wherein thealcohol of formula (C) is chosen from ethanol, n-propanol, isopropanol,n-butanol, sec-butanol, isobutanol, amyl alcohol, isopentanol, neopentylalcohol, methyl-n-propylcarbinol, hexan-1-ol, heptan-1-ol, octan-1-ol,nonan-1-ol, decan-1-ol, ethylene glycol.

According to another particular embodiment, the aforementioned imine ischosen from

The present invention also concerns a method of preparation of tertiaryamines of formula (E)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl, said tertiaryamine of formula (E) carrying in particular three differentsubstituents, different from a hydrogen atom;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,to obtain the compound of formula (E) as defined above.

According to the above embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E) comprising a step ofalkylation of an alcohol of formula (C) that can be a primary orsecondary alcohol on an imine of formula (D) that can be an aldimine ora ketimine.

According to a particular embodiment, the present invention relates to amethod of preparation of tertiary amines of formula (E)

wherein R₁ represents an aryl, allyl, C₁ to C₁₀ alkyl or C₃ to C₁₀cycloalkyl,R₂ represents a hydrogen,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,to obtain the compound of formula (E) as defined above.

According to another particular embodiment, the present inventionrelates to a method of preparation of tertiary amines of formula (E)

wherein R₁ and R₂ represent an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ toC₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,to obtain the compound of formula (E) as defined above.

According to a particular embodiment, the present invention relates to amethod of preparation of tertiary amines of formula (E)

wherein R₁ is an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl,R₂ represents a hydrogen,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl or a C₃ to C₁₀ cycloalkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,to obtain the compound of formula (E) as defined above.

According to a particular embodiment, the present invention relates to amethod of preparation of tertiary amines of formula (E)

wherein R₁ and R₂ represent an aryl, allyl, C₁ to C₁₀ alkyl, or C₃ toC₁₀ cycloalkyl,R₃ represents an aryl, allyl, alkyl C₁ to C₁₀ alkyl, C₃ to C₁₀cycloalkyl, a C₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,to obtain the compound of formula (E) as defined above.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E)

wherein the tertiary amine of formula (E) carries three differentsubstituents and wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ is C₂ to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the alcohol offormula (C) is chosen from ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, isobutanol, amyl alcohol, isopentanol, neopentyl alcohol,methyl-n-propylcarbinol, hexan-1-ol, heptan-1-ol, octan-1-ol,nonan-1-ol, decan-1-ol, ethylene glycol.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is catalyzed by an iron(0) complex.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is catalyzed, in particular by an iron(0) complex, chosenfrom the following formulas:

whereinTs=tosyl

TMS=trimethylsilyl

TBDMS=tert-butyldimethylsilyl

TIPS=triisopropylsilyl

and preferably being of the following formula (B):

in whichTBDMS=tert-butyldimethylsilyl

Ts=tosyl

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is catalyzed by the complex of formula (B).

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is catalyzed either by the complex of formula (B) formedprior to the preparation of tertiary amines, or the catalyst formed insitu during said preparation of tertiary amines by adding trimethylamineoxide to the complex of formula (A).

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is performed at a temperature of 80° C. to 130° C., andpreferably at 110° C.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is performed in an organic solvent.

Said organic solvent can be:

-   -   a single solvent chosen from ethanol, ethylene glycol,        tetrahydrofuran, dichloroethane, toluene, methoxycyclopentane,        diethyl ether.    -   a mixture of solvents chosen from the above mentioned solvents        or    -   the alcohol of formula (C) used as a solvent and as a reactant        in the method of preparation of tertiary amines of formula (E).

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the step ofalkylation is performed in ethanol or ethylene glycol used as solventand as reactant, or in a mixture of solvents composed in particular ofTHF and of ethanol or of ethylene glycol, ethanol or ethylene glycolbeing used as a solvent and reagent.

The use of ethanol, and more generally the alcohol of formula (C), bothas a solvent and as a reactant in this method of preparation of tertiaryamines of formula (E) makes it possible to carry out the reaction in thepresence of a large excess of one of the two reactants, which promotesthe reaction. The second interest is to avoid the use of anothersolvent, which makes the reaction more simple to implement and moreeconomic.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the primaryalcohol of formula (C), in particular ethanol or ethylene glycol is alsoused as solvent for the step of alkylation, in particular in a number ofequivalents higher than 10 equivalents, and preferably 85 equivalents.

The use of a solvent composed of primary alcohol of formula (C) inadmixture with another solvent in the method of preparation of tertiaryamines of formula (E) can be carried out according to thesolvent/primary alcohol (C) proportions ranging from 1/1 to 13/1.

When the primary alcohol of formula (C) is used both as solvent and asreactant in the method of preparation of tertiary amines of formula (E),at least 10 equivalents of primary alcohol of formula (C) are used andpreferably 85 equivalents.

When an organic solvent other than the primary alcohol of formula (C) isused, 3 equivalents of primary alcohol of formula (C) are used asreagent.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the concentrationof imine of formula (D) is comprised from 0.05 M to 0.4 M, in particularof 0.1 M, 0.2 M, 0.3 M, 0.4 M, and is preferably 0.2 M.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines formula (E), wherein the amount ofcatalyst is comprised from 1 to 20 mol %, in particular from 1 to 5 mol%, 5 to 10 mol %, 10 to 15 mol %, 15 to 20 mol %, and is preferably 5mol %, relative to the molar amount of imine.

According to a preferred embodiment, the invention relates to a methodof preparation of tertiary amines of formula (E), wherein the step ofalkylation is performed at a temperature of 110° C. for 24 hours inethanol with a concentration of imine of formula (D) of 0.2 M and aquantity of catalyst of 5 mol %.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), wherein the imine offormula (D) is either formed prior to the preparation of the tertiaryamines, or is formed in situ during said preparation of tertiary aminesby a method comprising contacting an aldehyde or ketone of formula (F)

wherein R₁, R₂ represents a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl, and an amine of formula (G)R₃—NH₂  (G)wherein R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀cycloalkyl, a C₁ to C₁₀ carbonyl derivative or a C₃ to C₁₀ formate.

According to the above embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a step ofpreparing tertiary amines of formula (E) comprising a step of alkylationof an alcohol of formula (C) to an imine of formula (D) wherein theimine of formula (D) is either formed prior to the preparation oftertiary amines, or formed in situ during said preparation of tertiaryamines by a method comprising contacting an aldehyde or a ketone offormula (F), and an amine of formula (G), the step of alkylation beingperformed in the presence of a catalyst of formula (B) either preformedor formed in situ in a first step prior to the step of alkylation.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a step ofpreparing tertiary amines of formula (E)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,in the presence of a catalyst of formula (B)

to obtain the compound of formula (E) as defined above, orcomprising a first step of preparing of the catalystcomprising a step of adding trimethylamine oxide on the complex offormula (A)

and a second step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl, onan imine of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl ora C₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate, in the presenceof a catalyst of formula (B) prepared during the preceding step and asdefined above,to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above, orcomprising a first step of preparing imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orcycloalkyl C₃ to C₁₀,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,comprising a step of contacting with an aldehyde or a ketone of formula(F)

wherein R₁ and R₂ are as defined above,and an amine of formula (G)R₃—NH₂  (G)wherein R₃ is as defined above,to obtain the imine of formula (D) as defined above;and a second step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl,on an imine of formula (D) prepared in the preceding step and as definedabove, in the presence of a catalyst of formula (B)

to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above, orcomprising a prior step of preparing of imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,comprising a step of contacting an aldehyde or ketone of formula (F)

wherein R₁ and R₂ are as defined above,and an amine of formula (G)R₃—NH₂  (G)wherein R₃ is as defined above,to obtain the imine of formula (D) as defined above;a prior step of preparing the catalystcomprising a step of adding trimethylamine oxide to the complex offormula (A):

said two prior steps may occur in any order,and a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl,on an imine of formula (D) prepared in the previous step

wherein R₁, R₂ and R₃ are as defined above,in the presence of catalyst of formula (B) prepared in the precedingstep and as above,to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a step ofpreparing tertiary amines of formula (E)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,R₄ represents a C₂ to C₁₀ alkyl or C₃ to C₁₀ cycloalkyl;comprising a step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ is as defined above,on an imine of formula (D)

wherein R₁, R₂ and R₃ are as defined above,in the presence of a catalyst of formula (B)

to obtain the compound of formula (E) as defined above.

According to a preferred embodiment, the invention relates to a methodof preparation of tertiary amines of formula (E), comprising a step ofalkylation of a primary alcohol of formula (C) to an imine of formula(D) in the presence of a catalyst of formula (B) formed prior to thepreparation of the tertiary amines.

According to a preferred embodiment, the invention relates to a methodof preparation of tertiary amines of formula (E), comprising a step ofalkylation of a primary alcohol of formula (C) to an imine of formula(D) in the presence of a catalyst of formula (B), the imine of formula(D) and the catalyst of formula (B) being formed prior to thepreparation of the tertiary amines.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a first stepof preparing of the catalyst,

comprising a step of addition of trimethyl amine oxide to the complex offormula (A)

and a second step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl,on an imine of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate, in the presenceof a catalyst of formula (B) prepared in the preceding step and asdefined above,to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a first stepof preparing imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀ formate,comprising a step of contacting with an aldehyde or a ketone of formula(F)

wherein R₁ and R₂ are as defined above,and an amine of formula (G)R₃—NH₂  (G)wherein R₃ is as defined above,to obtain the imine of formula (D) as defined above;and a second step of alkylation of an alcohol of formula (C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkyl,on an imine of formula (D) prepared in the preceding step and as definedabove, in the presence of a catalyst of formula (B)

to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above.

According to another embodiment, the invention relates to a method ofpreparation of tertiary amines of formula (E), comprising a prior stepof preparing of imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl orC₃ to C₁₀ cycloalkyl,R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, aC₁ to C₁₀ carbonyl derivative or a C₃ to C₁₀ formate,comprising a step of contacting an aldehyde or ketone of formula (F)

wherein R₁ and R₂ are as defined above,and an amine of formula (G)R₃—NH₂  (G)wherein R₃ is as defined above,to obtain the imine of formula of formula (D) as defined above;a prior step of preparing of the catalyst,comprising a step of adding trimethylamine oxide to the complex offormula (A):

said two prior steps may occur in any order,and a step of alkylation of a primary or secondary alcohol of formula(C)R₄OH  (C)wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀ cycloalkylon an imine of formula (D) prepared in the previous step

wherein R₁, R₂ and R₃ are as defined above,in the presence of catalyst of formula (B) prepared in the precedingstep and as defined above,to obtain the compound of formula (E)

wherein R₁, R₂, R₃, and R₄ are as defined above.

According to a preferred embodiment of the invention, the imine offormula (D) is chosen from:

The present invention also relates to novel tertiary amines having oneof the following formulas:

The present invention also concerns new tertiary amines of one of thefollowing formula:

Amines having long carbon chains, especially tertiary, are of greatindustrial interest. They are used in the synthesis of chemicalcompounds, as surfactants (corrosion inhibitors, detergents, flotationagents, emollients, softeners, antistatics, germicides, insecticides,dispersant, anti-caking agents, emulsifiers, lubricants, water treatmentagents, food additives, cosmetics, etc.).

Amines having long carbon chains, especially allylic, are fundamentalelements of organic chemistry and their synthesis is an importantindustrial and synthetic objective. The allyl amine moiety can be foundin natural products, but often, allylamine is converted into a range ofproducts by functionalization, reduction or oxidation of theinsaturation. Thus, amines can be used as raw materials for thesynthesis of many compounds such as amino acids, alkaloids andcarbohydrate derivatives.

Tertiary amines are important intermediates for the preparation ofasymmetric quaternary ammonium salts of formula

to access active agents whether for pharmaceutical or cosmetic use. Theyare used as surfactants, biocides for water treatment, flotation agent,petrol based detergent, corrosion inhibitors, processing rubberadditives or emulsifiers for herbicides.

EXAMPLES Example 1 Study of the Catalyst

TABLE 1 Tests with different iron catalysts

Ratio GC (starting/ Catalyst. Additive reduction/alkylation) Yield [%] AMe₃NO 0/0/100 97 B — 0/0/100 99

Example 2 Study of the Solvent

TABLE 2 Tests with different solvents

Temperature Ratio GC(starting/reduction/ Solvent [° C.]alkylation/dialkylation) DCE/EtOH  80 18/72/10/0 (svt/3 eq) THF/EtOH  8027/65/8/0 (svt/3 eq) THF/EtOH (1/1)  80 15/1/79/5 THF/EtOH (1/1) 11023/5/72/0 CPME/EtOH (1/2) 110 73/18/9/0

Example 3: Study of the Alcohol

TABLE 3 Study of several alcohols as alkylating agents

Ratio GC(starting/reduction/ Yield Catalyst Alcoolalkylation/dialkylation) [%] B ethylene glycol 0/0/100/0 18 B ethanol0/0/100/0 99

Example 4: Aromatic Imines

TABLE 4 Exemplification with various aromatic aldehydes, substituted inthe para position

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A/Me₃NO B 16/23/48/13 5/20/74/1 28 68

A/Me₃NO B 0/0/100/0 0/0/88/12 88 55

A/Me₃NO B 0/0/100/0 0/0/100/0 97 99

A/Me₃NO B B à 130° C. 35/25/40/0 45/37/18/0 6/39/55/0 33 15 50

A/Me₃NO B 3/50/35/12 8/13/75/4 26 68

A/Me₃NO B 48/33/19/0 0/0/86/14 12 74

A/Me₃NO B 34/19/43/4 0/0/84/16 54 85

A/Me₃NO B — 0/29/41/30 — 38

B 36/39/25/0 20

TABLE 5 Exemplification with various aromatic aldehydes

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A/Me₃NO B — 19/3/78/0 — 70

A/Me₃NO B — — 70 72

A/Me₃NO B 0/0/83/17 0/0/72/28 49 55

A/Me₃NO B 0/0/92/8 0/0/90/10 78 70

A/Me₃NO B — 5/0/90/5 — 78

A/Me₃NO B — 0/31/29/40 — 21

B 0/0/15/85 10

Example 5: Allylated Imines

TABLE 6 Exemplification with various conjugated aldehydes

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A/Me₃NO B — — 67

A/Me₃NO B — 48 30

Example 6: Alkylated Imines

TABLE 7 Exemplification with various aliphatic aldehydes

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A/Me₃NO B — 0/0/78/22 52 54

A/Me₃NO B — 0/40/17/43 — 14

Example 7: Aromatic Imines

TABLE 8 Exemplification with various aromatic amines

Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation)yield [%]

0/58/42/0 30

0/10/90/0 88

45/37/18/0 12 0/34/36/30 18

TABLE 9 Exemplification with various aliphatic amines

Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation)yield [%]

0/0/100/0 85

0/0/100/0 85

0/0/67/33 51

0/0/100/0 75

0/0/100/0 47

39/9/52/0 18

Example 8: Allylated Imines

TABLE 10 Exemplification with various substituted aromatic amines

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A/Me₃NO B — 0/0/100/0 — 57

A/Me₃NO B — 0/0/100/0 — 85

A/Me₃NO B — Incomplete conversion — 38

A/Me₃NO B — 0/0/100/0 — 88

A/Me₃NO B — 0/0/100/0 — 72

A/Me₃NO B — 0/0/100/0 — 55

A/Me₃NO B — 0/8/92/0 — 76

B 0/0/100/0 15

TABLE 11 Exemplification with various allylic or aliphatic amines

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

B 0/0/100/0 22

Example 9 Other Imines

TABLE 12 Exemplification with various imines

Ratio GC (starting/reduction/ Alkylation Product Catalystakylation/dialkylation) yield [%]

A B — 23/42/35/0 — 30

A B — 0/4/96/0 — 78

A B — 0/47/35/18 — 35

A B — 0/0/90/10 ou 0/0/83/17 — 71

A B — 0/27/73/0 (or starting 27) — 53

A B — 0/0/100/0 — 29

B 0/0/87/13 80 Cond A: [Fe] (5 mol %), Me₃NO (5 mol %), EtOH 110° C.Cond B: [Fe][MeCN] (5 mol %), EtOH 110° C.

Example 10: Intermolecular Version

TABLE 13 Optimization of the intermolecular version on the modelsubstrates

Ratio GC (starting/ Catalyst Additive Temperature [° C.]reduction/akylation/dialkylation) Yield [%] B — 110 0/0/68/32 65

TABLE 4 Exemplification of the intermolecular version of the reaction

Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation)yield [%]

18/0/34/48/ ou 0/18/34/48 10

48/0/34/19 26

0/0/54/46 35

51/0/29/20 19Alkylation Reactions of Imines (Conditions A)

In the glove box, catalyst A (0.05 eq.), trimethylamine oxide (0.05eq.), previously distilled and degassed ethanol (0.05 M) were introducedinto a tube equipped with a magnetic stirrer. The reaction mixture wasstirred at room temperature for 30 minutes. The substrate (50 mg, 1 eq.)was then added, the tube was sealed with a Teflon plug and removed fromthe glovebox. Thereafter, the reaction tube is immersed in a bathpreheated to 110° C. and stirred for 24 hours. After returning toambient temperature, the reaction is stopped by adding methanol (1 ml)and sodium hydroxide (1 ml, 1 M). The organic phases are extracted with3×5 ml of diethyl ether, washed with a saturated solution of sodiumchloride (5 ml), then dried over magnesium sulfate and concentratedunder reduced pressure. The crude product is purified by chromatographyon silica gel column (12 g SiO₂ already treated with 5% triethylamine,cyclohexane/ethyl acetate, 95/5) to obtain the desired alkyl amine.

Alkylation Reactions of Imines (Conditions B)

In a catalyst tube (10 ml), equipped with a magnetic stirrer, thesubstrate (50 mg, 1 eq.), the catalyst B (0.05 eq.) and ethanolpreviously distilled and degassed (0.05 M) are introduced. The tube wasplaced under argon and then sealed with a Teflon stopper. Thereafter,the reaction tube is immersed in a bath preheated to 110° C. and stirredfor 24 hours. After returning to ambient temperature, the reaction isstopped by adding methanol (1 ml) and sodium hydroxide (1 ml, 1 M). Theorganic phases were extracted with 3×5 ml of diethyl ether, washed witha saturated solution of sodium chloride (5 ml), then dried overmagnesium sulfate and concentrated under reduced pressure. The crudeproduct is purified by chromatography on silica gel column (12 g SiO₂already treated with 5% triethylamine, cyclohexane/ethyl acetate, 95/5)to obtain the desired alkyl amine.

The invention claimed is:
 1. A method of preparation of unsymmetricaltertiary amines comprising using an alcohol and an imine as reactants,wherein the alcohol is a primary or secondary alcohol of formula (C)R₄OH  (C) wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀cycloalkyl, and wherein the imine is an imine of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl, R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃to C₁₀ cycloalkyl, a C₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀formate, wherein the tertiary amines are of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above, wherein the tertiaryamines carry three different substituents, said method comprising a stepof alkylation of an alcohol of formula (C)R₄OH  (C) on an imine of formula (D)

to obtain the compound of formula (E) wherein the step of alkylation iscatalyzed by an iron(0) complex.
 2. The method according to claim 1,wherein the iron(0) complex is chosen from the following formulas:

wherein Ts=tosyl

TMS=trimethylsilyl

TBDMS=tert-butyldimethylsilyl

TIPS=triisopropylsilyl

or the following formula (B):

in which TBDMS=tert-butyldimethylsilyl

Ts=tosyl


3. The method according to claim 1, wherein the step of alkylation iscatalyzed either by the complex of formula (B) formed prior to thepreparation of tertiary amines,

in which TBDMS=tert-butyldimethylsilyl

Ts=tosyl

or by the catalyst formed in situ during said preparation of tertiaryamines by adding trimethylamine oxide to the complex of formula (A)


4. The method according to claim 1, wherein the step of alkylation isperformed in an organic solvent, or in ethanol, or ethylene glycol, orin a mixture of solvents, or in a mixture of solvents composed of THFand of ethanol or of ethylene glycol.
 5. The method according to claim1, wherein the primary alcohol of formula (C), is also used as solventfor the step of alkylation.
 6. The method according to claim 1, whereinthe primary alcohol of formula (C), is also used as solvent for the stepof alkylation, in a number of equivalents higher than 10 equivalents. 7.The method according to claim 1, wherein the imine of formula (D) iseither formed prior to the preparation of the tertiary amines, or isformed in situ during said preparation of tertiary amines by a methodcomprising contacting an aldehyde or ketone of formula (F)

wherein R₁, R₂ represents a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl, and an amine of formula (G)R₃—NH₂  (G) wherein R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃ toC₁₀ cycloalkyl, a C₁ to C₁₀ carbonyl derivative or a C₃ to C₁₀ formate.8. The method according to claim 1, wherein the step of alkylation isperformed in the presence of a catalyst of formula (B)

to obtain the compound of formula (E) as defined above, or comprising afirst step of preparing of the catalyst comprising a step of addingtrimethylamine oxide on the complex of formula (A)

and a second step of alkylation of an alcohol of formula (C)R₄OH  (C) wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀cycloalkyl, on an imine of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl ora C₃ to C₁₀ cycloalkyl, R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl,C₃ to C₁₀ cycloalkyl, a C₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀formate, in the presence of a catalyst of formula (B) prepared duringthe preceding step and as defined above, to obtain the compound offormula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above, or comprising a firststep of preparing imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orcycloalkyl C₃ to C₁₀, R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃to C₁₀ cycloalkyl, a C₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀formate, comprising a step of contacting with an aldehyde or a ketone offormula (F)

wherein R₁ and R₂ are as defined above, and an amine of formula (G)R₃—NH₂  (G) wherein R₃ is as defined above, to obtain the imine offormula (D) as defined above; and a second step of alkylation of analcohol of formula (C)R₄OH  (C) wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀cycloalkyl, on an imine of formula (D) prepared in the preceding stepand as defined above, in the presence of a catalyst of formula (B)

to obtain the compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above, or comprising a priorstep of preparing of imines of formula (D)

wherein R₁ and R₂ represent a hydrogen, aryl, allyl, C₁ to C₁₀ alkyl, orC₃ to C₁₀ cycloalkyl, R₃ represents an aryl, allyl, C₁ to C₁₀ alkyl, C₃to C₁₀ cycloalkyl, a C₁ to C₁₀ carbonyl derivative, or a C₃ to C₁₀formate, comprising a step of contacting an aldehyde or ketone offormula (F)

wherein R₁ and R₂ are as defined above, and an amine of formula (G)R₃—NH₂  (G) wherein R₃ is as defined above, to obtain the imine offormula (D) as defined above; a prior step of preparing the catalystcomprising a step of adding trimethylamine oxide to the complex offormula (A):

said two prior steps may occur in any order, and a step of alkylation ofan alcohol of formula (C)R₄OH  (C) wherein R₄ represents a C₂ to C₁₀ alkyl, or a C₃ to C₁₀cycloalkyl, on an imine of formula (D) prepared in the previous step

wherein R₁, R₂ and R₃ are as defined above, in the presence of catalystof formula (B) prepared in the preceding step and as above, to obtainthe compound of formula (E)

wherein R₁, R₂, R₃ and R₄ are as defined above.
 9. The tertiary amineshaving one of the following formulae: